N-Aryl oxazolidinones, oxazolidinethiones, pyrrolidinones, pyrrolidines and thiazolidinones

ABSTRACT

N-aryl oxazolidinones, oxazolidinethiones, pyrrolidinones, pyrrolidines and thiazolidinones are disclosed. These compounds possess antidepressant activity.

This is a division, of application Ser. No. 45,143, filed June 4, 1979 now U.S. Pat. No. 4,348,393.

The present invention relates to N-aryl-oxazolidinones, oxazolidinethiones, pyrrolidinones, pyrrolidines and thiazolidinones, their process of preparation and their therapeutic application.

The compounds of the invention have the formula: ##STR1## in which the parameters (X, A, R₁) take anyone of the following values: (a) (O,O,H), R₂ is:

either an ester group of formula --CH₂ --OCOR₃ in which R₃ is a linear or branched alkyl moiety having from 1 to 8 carbon atoms, a cyclohexyl group, a phenyl nucleus, a methoxymethyl or a phenyloxymethyl group; and R is in para position and is anyone of the following groups: n-butyloxy, methyl-3 butyloxy, cyclopentylmethoxy, cyclohexylmethoxy, cyano-2 ethoxy, cyanomethoxy, benzyloxy of formula ##STR2## in which R₄ is a hydrogen or a chlorine atom in meta position, a fluorine atom in meta or para position, or a cyano or nitro group in meta position; disubstituted para-benzyloxy group of formula ##STR3## in which R₅ is a chlorine atom or a cyano group;

or an ether group of formula --CH₂ --OR₆ in which R₆ is a linear or branched alkyl group having from 1 to 5 carbon atoms, a cyclohexyl, allyl, propargyl or methoxymethyl group; and R is the methyl group in meta position, or is anyone of

the following groups located in para position:

linear or branched alkyloxy having from 4 to 6 carbon atoms,

cycloalkylmethyloxy the cycloalkyl moiety of which has from 4 to 7 carbon atoms,

(methyl-1 cyclopentyl-1)methyloxy,

(cyclopentene-1 yl ) methyloxy,

(cyclohexene-1 yl ) methyloxy,

(butene-2) oxy,

(methyl-3 butene-2) oxy,

chloro-4 butyloxy,

cyano-2 ethoxy; cyano-3 propoxy or cyano-4 butoxy,

oxo-2 propoxy,

(oxo-4 cyclohexyl-1) methoxy,

morpholino-2 ethoxy,

N,N dimethyl amino,

(tetrahydropyranyl-4) methoxy or (tetra hydropyranyl-3) methoxy,

benzyloxy of formula ##STR4## in which R₇ is selected from the group consisting of: H, 3--Cl, 4--Cl, 3--F, 4--F, 3--I, 3--Br, 3--CF₃, 3--NO₂, 4--NO₂, 4--CN,

3-cyanobenzyloxy, the corresponding compound of formula (I) having an asymmetric carbon being isolated as a racemic mixture or as two enantiomers or formulae (Ia) and (Ib) having respectively the absolute configuration: R(-) and S(+) ##STR5## disubstituted benzyloxy of formula ##STR6## in which R₈ is a chlorine atom, or a cyano or nitro group; disubstituted benzyloxy of formula ##STR7## in which R₉ is a chlorine atom or a nitro group; disubstituted benzyloxy of formula ##STR8## in which R₅ is a chlorine atom or a cyano group; 3,5-dichlorobenzyloxy;

substituted or non substituted styryl chain of trans configuration and of formula ##STR9## in which R₁₀ is a hydrogen or chlorine atom, or a cyano or nitro group;

substituted or non substituted styryl chain of cis configuration and of formula ##STR10## in which R₁₁ is a hydrogen atom or a nitro group, ##STR11## or phenethyl chain, or phenyl nucleus;

or an amine group of formula ##STR12## is selected from the group consisting of: ##STR13## and R is in para position and is selected from the group consisting of: n-butyloxy, methyl-3 butyloxy, cyclopentylmethoxy, cyclohexylmethoxy, cyanomethoxy or cyano-2 ethoxy group;

benzyloxy group of formula ##STR14## in which R₁₄ has one of the following values: H, 3--Cl, 4--F, 3--CN, 3--NO₂ ; or

disubstituted benzyloxy group of formula ##STR15##

(b) (O,CH₂,H), R₂ is the hydroxymethyl group, and R is the para-(metanitro) benzyloxy group;

(c) (H₂,CH₂,H), R₂ is the hydroxymethyl group and R is the parabenzyloxy group;

(d) (O,S,H), R₂ is the methoxymethyl group and R is the para-(metanitro) benzyloxy group;

(e) (S,O,H), R₂ is:

either a hydroxymethyl group and R in para position is selected from the group consisting of:

a linear or branched alkyloxy group having from 2 to 5 carbon atoms,

a cyclopentylmethoxy, cyclohexylmethoxy, (cyclohexene-1 yl) methoxy or (tetrahydropyranyl-4) methoxy group,

a cyanomethoxy, cyano-2 ethoxy, cyano-3 propoxy or cyano-4 butoxy group,

a benzyloxy group of formula ##STR16## in which R₁₅ has one of the following values: 3--Cl, 4--Cl, 3--F, 4--F, 3--NO₂, 3--CN, 3--CF₃, or

a disubstituted benzyloxy group of formula: ##STR17##

or an ether group of formula --CH₂ --O--R₁₆ in which R₁₆ is a linear or branched alkyl group having from 1 to 3 carbon atoms, and R in para position is selected from the group consisting of:

methyl-3 n-butyloxy, cyclopentylmethoxy, cyclohexylmethoxy or cyano-4 butoxy group),

a benzyloxy group of formula ##STR18## in which R₁₇ is a cyano or nitro group the cyano-3 nitro-5 benzyloxy group, or

the pyridinyl-3 methoxy group,

or an ester group of formula --CH₂ --OCOR₁₈ in which R₁₈ is a methyl or ethyl group and R in para position is the cyclohexylmethoxy gru or a benzyloxy group of formula ##STR19## in which R₁₇ is a cyano or nitro group.

(A) The process for preparing the compounds of formula (I) in which the parameters (X,A,R₁,R₂) represent (O,O,H, CH₂ OCOR₃), R₃ having the same meanings as above, consists in condensing the compounds of formula: ##STR20## in which R₁₉ represents one of the following groups: n-butyloxy; methyl-3 butoxy; cyclopentylmethoxy; cyclohexylmethoxy; cyano-2 ethoxy; cyanomethoxy; benzyloxy of formula ##STR21## with R₄ =H, 3--Cl, 3--F, 4--F, 3--CN or 3--NO₂ ; and benzyloxy of formula ##STR22## with R₅ =Cl or CN, with the acid chlorides of formula:

    R.sub.3 COCl                                               (III)

in which R₃ has the same meanings as above.

This condensation is carried out preferably at room temperature, either in an organic solvent such as chloroform or tetrahydrofuran in the presence of triethylamine, or in pyridine.

The compounds of formula (II), except those in which R₁₉ is the cyano-2 ethoxy group, are prepared according to the method described in Belgian Pat. No. 851 893 (reacting the p-hydroxyphenyl-3 hydroxymethyl-5 oxazolidinone-2 on the suitable chloride, bromide or tosylate).

The compounds of formula (II) in which R₁₉ is the cyano-2 ethoxy group is obtained by cyclising, by action of ethyl carbonate, the compound of formula ##STR23## to obtain the compound of formula: ##STR24## which is selectively hydrogenolysed in the presence of palladium on charcoal, in ethanol, preferably at room temperature to give the compound of formula: ##STR25## which is condensed with acrylonitrile in the presence of triton B, to give the compound of formula: ##STR26## which is then hydrogenolysed in ethanol in the presence of palladium on charcoal, and preferably, of some drops of hydrochloric ethanol.

The compound of formula (IV) is obtained in condensing, in methanol or ethanol, the parabenzyloxyaniline with the benzyloxy-3 epoxy-1,2 propane.

(B) The process for preparing the compounds of formula (I) in which the parameters (X,A,R₁) represents (O,O,H), and R₂ is an ether group of formula --CH₂ --OR₆ in which R₆ has the same meanings as above consists:

(1) either in submitting the compounds of formula: ##STR27## in which R₂₀ represents the meta-methyl group or one of the following groups in para position: linear or branched alkyloxy having from 4 to 6 carbon atoms; cycloalkylmethoxy the alkyl moiety of which has from 4 to 7 carbon atoms; (methyl-1 cylcopentyl-1) methoxy; butene-2 oxy; methyl-3 butene-2 oxy; (cyclopentene-1 yl) methoxy; (cyclohexene-1 yl) methoxy; morpholino-2 ethoxy; chloro-4 butyloxy; (oxo-4 cylcohexyl-1) methoxy; oxo-2 propoxy; cyano-3 propoxy; cyano-2 ethoxy; cyano-4 butoxy; dimethyl amino; (tetrahydropyranyl-4) methoxy; (tetrahydropyranyl-3) methoxy;

benzyloxy of formula ##STR28## in which R₇ =H, 3--Cl, 4--Cl, 3--F, 4--F, 3--I, 3--Br, 3--CF₃, 3--NO₂, 4--NO₂, 3--CN, 4--CN; disubstituted benzyloxy of formula: ##STR29## in which R₈, R₉ and R₅ have the same meanings as above; and ##STR30## to a so-called "phase transfer" reaction, in the presence of a catalyst so-called "phase transfer catalyst", and in a basic medium with derivatives of formulae: ##STR31## in which R₆ has the same meanings as previously.

The used catalyst is preferably the benzyltributylammonium bromide, but it can be chosen among the catalysts mentioned in the following documents: --Synthesis 1973, 441, and Angewandte Chemie, Edit. Int. Vol. 13, 170, (1974).

The used base is preferably aqueous soda and the reaction can be carried out in an organic solvent such as methylene chloride or benzene.

The compounds of formula (IIa), except those in which R₂₀ represents the cyano-2 ethoxy group which is obtained by hydrogenolysing the compound of formula (VII), are prepared according to the method described in Belgian Pat. No. 851 893.

(2) or in condensing the compounds of formula: ##STR32## in which R'₆ is a linear or branched alkyl group having from `to 5 carbon atoms, a cylcohexyl or a methoxymethyl group, with the chlorides or tosylates of formula: ##STR33## in which R'₂₀ has the same meanings as R₂₀ except for the meta-methyl and paracyano-2 ethoxy groups.

The condensation is carried out with reflux in acetone or acetonitrile in the presence of potassium carbonate, or with reflux in dimethylformamide in the presence of sodium hydride.

The compounds of formula (VIII) are obtained by hydrogenolysing in the presence of palladium on charcoal, the compounds of formula: ##STR34## in which R'₆ has the same meanings as in formula (VIII).

The compounds of formula (IX) are obtained by a three stage synthesis which consists in condensing the chlorhydrine of formula: ##STR35## in which R'₆ has same meanings as in formula (IX) with phosgene, then in condensing product thus obtained with parabenzyloxyaniline and at last in cyclising the obtained product by means of ethanolic potash or sodium methylate in methanolic solution.

(3) or, when R is the cyano-2 ethoxy group, in reacting acrylonitrile in the presence of triton B with the compound of formula (VIII);

(4) or, according to the process described above for the synthesis of compounds of formula (IX), but with chlorohydrines of formula (X) and anilines of formula: ##STR36## in which R₂₁ represents a trans styryl group of formula ##STR37## with R₁₀ =H, Cl, CN, NO₂ ; a cis styryl group of formula ##STR38## with R₁₁ =H, NO₂ ; a stylbene group ##STR39## a phenethyl group; or a phenyl group; instead of the parabenzyloxyanoline;

(5) or, when (I) is (Ia) in submitting to a "phase transfer" reaction the compound of absolute configuration R(-) and having the formula: ##STR40## in presence of a phase transfer catalyst, of (CH₃)₂ SO₄ and in a basic medium.

The compound of formula (IIb) is obtained by reacting the metacyanobenzyl chloride with the compound of formula: ##STR41## which is obtained by hydrogenolysing in the presence of palladium on charcoal, the compound of absolute configuration R(-) and having the formula: ##STR42##

This last compound is obtained according to the method described for the synthesis of compounds of formula (IX) but from parabenzyloxyaniline and benzyloxy-3 paratosyloxy-1 propanol-2 having the S(+) configuration, instead of the compound of formula (X).

(6) or, when (I) is (Ib), according to the process described for the synthesis of the compounds of formula (IX), but by using p-(cyano-3) benzyloxyaniline instead of parabenzyloxyaniline and methocy-3 paratosyloxy-1 propanol-2 of absolute configuration R and of formula: ##STR43## instead of the compound of formula (X).

The compound of formula (XII) is obtained by reacting the tosyl chloride, in a benzene medium and in the presence of pyridine, with the methoxy-3 propane diol-1,2 of absolute configuration S and of formula: ##STR44##

This compound of formula (XIII) is obtained by catalytically debenzylating, in the presence of palladium on charcoal, the compound of absolute configuration R and of formula: ##STR45##

The compound of formula (XIV) is obtained by opening, with methanol in the presence of boron trifluoride etherate, benzyloxy-1 epoxy-2,3 propane having the absolute configuration S(+) and described in J. Chem. Soc. 1967 1021.

(C) The process for preparing the compounds of formula (I) in which the parameters (X,A,R₁) represent (O,O,H), R₂ represents an amine group of formula ##STR46## has the same meanings as above, consists in reacting amines of formula ##STR47## with the compounds of formula: ##STR48## in which R₂₂ is a n-butyloxy, methyl-3 butyloxy, cyclopentylmethoxy, cyclohexylmethoxy, cyanomethoxy, cyanoethoxy group, benzyloxy group of formula ##STR49## in which R₁₄ has the same meaning as above or a chloro-3-nitro-5 benzyloxy group.

The compounds of formula (XV) are obtained by action of mesyl chloride on the compounds of formula: ##STR50## in which R₂₂ has the same meanings as in formula (XV), the compounds of formula (IId) being obtained according to the process described in Belgian pat. No. 851 893.

(D) The process for preparing the compounds of formula (I) in which the parameters (X, A, R₁) represent (O,CH₂,H), R₂ represents the hydroxymethyl group and R represents the para(metanitro) benzyloxy group consists in reacting metanitrobenzyl chloride on the compound of formula: ##STR51## obtained by hydrogenolysing in the presence of palladium on charcoal, the compound of formula: ##STR52## obtained by reducing with lithium borohydride the compound of formula: ##STR53##

The compound of formula (XVIII) is obtained by esterifying with ethanol in the presence of sulfuric acid, the compound of formula: ##STR54## which is obtained by condensing parabenzyloxyaniline with itaconic acid.

The process for preparing the compound of formula (I) in which (X,A,R₁) is (H₂, CH₂,H), R₂ is the hydroxymethyl group and R is the parabenzyloxy group consists in reducing with lithium aluminium hydride the compound of formula (XVIII).

(E) The process for preparing the compound of formula (I) in which (X, A,R₁) is (O,S,H), R₂ is the methoxymethyl group and R is the para(metanitro) benzyloxy group consists in cyclising with phosgene the compound of formula: ##STR55## obtained by condensing para(metanitro)benzyloxyaniline with methoxy methyl-2 thioxirane.

(F) The process for preparing the compounds of formula (I) in which the parameters (X,A,R₁) are (S,O,H), R₂ is a hydroxymethyl group or a --CH₂ OR₁₆ group in which R₁₆ has the same meanings as above, consists in cyclising with thiophosgene, either compounds of formula: ##STR56## in which R₂₃ represents a linear or branched alkyloxy group having from 2 to 5 carbon atoms, cyclopentylmethoxy, cyclohexylmethoxy, (cyclohexane-1 yl) methoxy, (tetrahydropyrannl-4)methoxy, cyanomethoxy, cyano-2 ethoxy, cyano-3 propoxy, cyano-4 butoxy group, benzyloxy group of formula ##STR57## with R₁₅ =3--Cl, 4-Cl, 3--F, 4--F, 3--NO₂, 3--CN or C--CF₃, (chloro-3 cyano-5) benzyloxy or (cyano-3 fluoro-4) benzyloxy group, -- or compounds of formula: ##STR58## in which R₁₆ has the same meaings as above and R₂₄ represents a methyl-3 butoxy; cyclopentylmethoxy, cyclohexylmethoxy, cyano-4 butoxy group, a benzyloxy group of formula ##STR59## with R₁₇ =CH or NO₂, a (cyano-3 nitro-5) benzyloxy or (pyrindinyl-3) methoxy group.

The compounds of formula (XXI) are obtained by condensing glycidol and anilines of formula: ##STR60## in which R₂₃ has the same meanings as in formula (XXI), and the compounds of formula (XXII) are obtained by condensing anilines of formula: ##STR61## in which R₂₄ has the same meanings as in formula (XXII) with the chlorohydrines of formula: ##STR62## in which R₁₆ has the same meaning as above.

(G) The process for preparing the compounds of formula (I) in which the parameters (X,A,R₁) represent (S,O,H) and R₂ is an ester group of formula R₁₈ COO CH₂ in which R₁₈ has the same meaning as above, consists in condensing the acid chloride of formula:

    R.sub.18 COCl                                              (IIIa)

in which R₁₈ is as above, with the compounds of formula (I) having the following structure: ##STR63## in which R₂₅ represents a cyclohexylmethoxy group or a benzyloxy group of formula ##STR64## with R₁₇ =CN or NO₂, according to the process described under chapter (A) above. The compounds (Ic) are obtained according to the process described under chapter (F) above.

The following preparations are given by way of example to illustrate the invention.

EXAMPLE I Para (meta-nitrobenzyloxy) phenyl-3 acetoxy-methyl-5 oxazolidinone-2 [I]

Code number: 36.

A solution of 10.5 g of para(metanitrobenzyloxy)phenyl-3 hydroxy methyl-5 oxazolidinone-2 [(II), mp=135° C.], 2.5 cm³ of acetyl chloride and 4.5 cm³ of triethylamine in 100 cm ³ of chloroform was left for 12 hours at room temperature. Then, the solution was diluted in water, the chloroformic phase was decanted, the solvent was evaporated and the residue was recrystallized in pure alcohol. 8 g of product were obtained.

    ______________________________________                                         Yield:                72%                                                      Melting point:        126° C.                                           Empirical formula:    C.sub.19 H.sub.18 N.sub.2 O.sub.7                        Molecular weight:     386.35                                                   Elementary analysis:                                                                      C         H      N                                                  ______________________________________                                         Calculated (%)                                                                              59.06       4.70   7.25                                           Found (%)    59.10       4.56   6.95                                           ______________________________________                                    

With the same method, but from the corresponding reagents, the compounds of formula (I) were prepared, given in table I and bearing code numbers: 1 to 44; 103 to 108; 115, 117, 120 to 141; 178 and 208.

EXAMPLE 2 (paracyano-2 ethoxyphenyl)-3 hydroxymethyl-5 oxazolidinone-2 [II] ##STR65## First Step: (p-benzyloxyphenyl)-3 benzyloxymethyl-5 oxazolidinone-2 [V]

This compound was obtained following a method in which a mixture of 0.2 mole of the compound of formula: ##STR66## 200 ml of ethyl carbonate and 8 ml of triethylamine is heated at 100°-110° C. for 5 hours, then the product was filtered and recrystallized in pure alcohol.

    ______________________________________                                         Yield:                80%                                                      Melting point:        126° C.                                           Empirical formula:    C.sub.24 H.sub.23 NO.sub.4                               Molecular weight:     389.43                                                   Elementary analysis:                                                                      C         H      N                                                  ______________________________________                                         Calculated (%)                                                                              74.02       5.95   3.60                                           Found (%)    73.87       6.14   3.89                                           ______________________________________                                    

Second step: (p-hydroxyphenyl)-3 benzyloxymethyl-5 oxazolidinone-2 (VI)

A suspension of 18 g (0.046 mole) of the compound obtained in the first step and 2 g of 10% palladium charcoal in 400 ml of pure alcohol was hydrogenolysed in autoclave, at room temperature and under a hydrogen pressure of 4-5 kg. Then the mixture was filtered, the solvent evaporated and the residue recrystallized in pure alcohol.

    ______________________________________                                         Yield:                73%                                                      Melting point:        153° C.                                           Empirical formula:    C.sub.17 H.sub.17 NO.sub.4                               Elementary analysis:                                                                      C          H      N                                                 ______________________________________                                         Calculated (%)                                                                              68.21        5.73   4.68                                          Found (%)    68.38        5.62   4.46                                          ______________________________________                                    

By the same process, but from the corresponding reagents, the compound of formula (IIc) [mp=188° C., Empirical formula: C₁₀ H₁₁ NO₄ ] (from compound of formula (Va)); and the compound of formula (XVI) [mp=196° C., empirical formula: C₁₁ H₁₃ NO₃ ] (from compound of formula (XVII)) were obtained.

Third step: (p-cyanoethoxy-2-phenyl)-3-benzyloxymethyl-5 oxazolidinone-2 (VII)

A solution of 13 g (0.03 mole) of the compound prepared in the second step, in 45 g (0.86 mole) of acrylonitrile in the presence of 1 ml of triton B (40% in methanol), was brought to reflux for 15 hours. Then the acrylonitrile in excess was evaporated, the residue was taken up in 100 ml of N soda and filtered, the precipitate was washed with water then with ether and recrystallized in methanol.

    ______________________________________                                         Yield                 60%                                                      Melting point:        112° C.                                           Empirical formula:    C.sub.20 H.sub.20 N.sub.2 O.sub.4                        Elementary analysis:                                                                      C          H      N                                                 ______________________________________                                         Calculated (%)                                                                              68.17        5.72   7.95                                          Found (%)    67.89        5.66   8.21                                          ______________________________________                                    

By the same method, but from the corresponding reagents, the compounds of formula (I) were prepared, given in table (I) and bearing code numbers 52 to 54 and 145 to 147.

Fourth step: (p-cyano-2 ethoxyphenyl)-3 hydroxymethyl-5 oxazolidinone-2 (II) ##STR67##

A suspension of 3.5 g (0.01 mole) of (p-cyano-2 ethoxyphenyl)-3 benzyloxymethyl-5 oxazolidinone-2, obtained in the preceding step, 0.4 g of 10% palladium charcoal and 0.05 ml of 7.5 N chlorhydric ethanol in 250 ml of dioxane, was hydrogenolysed in an autoclave, at a pressure of 1 kg of hydrogen and at room temperature. The mixture was filtered, the residue was purified by chromatography on a silica column. Eluted with the mixture chloroform-acetone 50/50, the product was obtained which was recrystallized in pure alcohol. Weight: 1 g.

    ______________________________________                                         Yield:              39%                                                        Melting point:      131° C.                                             Empirical formula:  C.sub.13 H.sub.14 N.sub.2 O.sub.4                          Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              59.53       5.38   10.68                                          Found (%)    59.06       5.24   10.37                                          ______________________________________                                    

EXAMPLE 3 para (meta-nitrobenzyloxy) phenyl-3 methoxymethyl-5 oxazolidinone-2 (I)

Code number: 61.

A mixture of 10.3 g of para (metanitrobenzyloxy) phenyl-3 hydroxymethyl- 5 oxazolidinone (IIa), 10.7 g of benzyltributylammonium bromide, 14.2 g of methyl iodide and 1.8 g of NaOH in 200 ml of water and 280 ml of methylene chloride, was brought to reflux for 50 hours. Then the mixture was decanted, the organic layer washed with water, the solvent evaporated, the residue taken up in ethyl acetate, the filtrate was filtered and chromatographied on a silica column; eluted with chloroform, 6.9 g of the product was obtained which was recrystallized in isopropanol.

    ______________________________________                                         Yield:              62%                                                        Melting point:      78° C.                                              Empirical formula:  C.sub.18 H.sub.18 N.sub.2 O.sub.6                          Molecular weight:   358.34                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              60.33       5.06   7.82                                           Found (%)    60.52       5.10   7.92                                           ______________________________________                                    

By the same method, but from the corresponding reagents, the compounds of formula (I) were prepared, given in table (I) and bearing code numbers 45, 46, 55 to 57; 59, 64 to 73; 109 to 112; 142 to 156; 159 to 169; 179 to 186; 188, 197, 198 and 199 (Ia).

EXAMPLE 4 para-n-butyloxy phenyl-3 isopropyloxymethyl-5 oxazolidinone-2 (I) Code number: 47 First step: para benzyloxyphenyl-3 isopropyl oxymethyl-5 oxazolidinone:2 (IX)

Code number: 225.

To a solution of 59 g of phosgene in 560 ml of dichloroethane was added 83.4 g of chloro-1 isopropyloxy-3 propanol-2 (X), then in 30 minutes a solution of 81.9 g of N, N-diethylaniline in 160 ml of dichloroethane. The mixture was heated to 50° C. for 2 hours, 250 ml of water was added, the organic layer was decanted and added in 30 minutes on 271.5 g of para benzyloxyaniline. The mixture was brought to reflux for 3 hours, filtered, washed with a 1 N hydrochloric acid solution, with water, dried, the solvent was evaporated and the residue was recrystallized in ethanol. 165.5 g of the product were obtained.

    ______________________________________                                         Yield:    81%                                                                  Melting point:                                                                           107° C.                                                       NMR spectrum:                                                                            δ ppm (DMSO)                                                             9.80,s,NHCOO         1 proton                                                  7.40,s,and 5.08,s:   7 protons                                                 7.18,m,aromatic protons                                                                             4 protons                                                  ##STR68##           1 proton                                                  3.85,d, (J = 5Hz) CH.sub.2O                                                                         2 protons                                                 3.59,m, ClCH.sub.2CH 3 protons                                                  ##STR69##           6 protons                                       IR spectrum:                                                                             band NHCOO at 1700 and                                                         3305 cm.sup.-1                                                       ______________________________________                                    

A solution of 165.5 g of this compound and 29.3 of potash in 2.4 liters of ethanol was brought to 50° C. for 3 hours. Then the solvent was evaporated, the residue was taken up in chloroform, washed with water, dried and the solvent was evaporated. The residue was crystallized in ether and recrystallized in dioxane. 113 g of product were obtained.

    ______________________________________                                         Yield:               75%                                                       Melting point:       110° C.                                            Empirical formula:   C.sub.20 H.sub.23 NO.sub.4                                Molecular weight:    341.4                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              70.36       6.79   4.10                                           Found (%)    70.14       6.49   4.22                                           ______________________________________                                    

By the same method, but from the corresponding reagents, the compounds of formula (IX) were prepared, given in table (II) and bearing code numbers 226 to 229; as well as:

the compounds of formula (I) given in table I and bearing code numbers 187, 189 to 196,

the compound of formula (Ib) given in table I and bearing code number 20, and

the compound of formula (Va): mp=100° C.; Yield: 93%;

Empirical formula: C₂₄ H₂₃ NO₄ ;[α]_(D) ²¹ =-33° 5 (C=1, CH₂ Cl₂).

Second step: parahydroxyphenyl-3 isopropyloxymethyl-5 oxazolidinone-2 (VIII)

Code number: 221.

85 g of the compound prepared in the first step in 1700 ml of dioxane and 15 ml of 6.5 N hydrochloric alcohol, in the presence of 8.5 g of 10% palladium charcoal, were hydrogenolysed in an autoclave at a pressure of 6 kg for 6 hours. Then the mixture was filtered, the solvent was evaporated, the residue was crystallized in ether and recrystallized in toluene. 43.7 of product were obtained.

    ______________________________________                                         Yield:               70%                                                       Melting point:       93° C.                                             Empirical formula:   C.sub.13 H.sub.17 NO.sub.4                                Molecular weight:    251.3                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              62.14       6.82   5.57                                           Found (%)    62.14       6.80   5.56                                           ______________________________________                                    

By the same method, but from the corresponding reagents, the compounds of formula (VIII) were prepared, given in table III and bearing code numbers: 222 to 224 and 230 to 232.

Third step: para n-butyloxyphenyl-3 isopropyloxy methyl-5 oxazolidinone-2 (I)

Code number: 47.

To a solution of 8.7 g of the compound obtained in the preceding step in 150 ml of dimethyl formamide, was added 1.68 g of sodium hydride (50%), then 9.7 g of n-butyl chloride. The mixture was brought to 100° C. for 2 hours and 30 mn, then the solvent was evaporated, the residue was taken up in chloroform, washed with water, dried, the solvent was evaporated, the residue was crystallized in isopropyl ether and recrystallized in isopropanol. 7.8 g of product were obtained.

    ______________________________________                                         Yield:               73%                                                       Melting point:       77° C.                                             Empirical formula:   C.sub.17 H.sub.25 NO.sub.4                                Molecular weight:    307.4                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              66.42       8.20   4.56                                           Found (%)    66.19       8.27   4.36                                           ______________________________________                                    

By the same method, but from the corresponding reagents, the compounds of formula (I) were prepared, given in table I and bearing the following code numbers: 48, 50, 51, 58, 60, 62, 63, 142, 143, 152, 153, 157, 158, 160, 99 and 234, as well as the compound Formula (IIb): mp=132° C.; Yield: 97%; [α]_(D) ²⁰ =-79° 2 (C=1, pyridine: Empirical formula: C₁₈ H₁₆ N₂ O₄ ;

    ______________________________________                                         Elementary analysis:                                                                      C         H      N                                                  ______________________________________                                         Calculated (%)                                                                              66.66       4.97   8.64                                           Found (%)    66.54       5.01   8.54                                           ______________________________________                                    

EXAMPLE 5 p-toluene sulfonyloxy-1 hydroxy-2 methoxy-3 propane (R configuration) (XII) First step: methoxy-1 hydroxy-2 benzyloxy-3 propane R(+) (XIV)

To a solution of 4.14 g of benzyloxy-3 epoxy-1,2 propane in 40 ml of methanol, cooled to 5° C., were added 3 drops of boron trifluoride etherate. Then the mixture is left so as to reach slowly the room temperature (3 hours). A few gms. sodium bicarbonate was added, the solvent was evaporated, the residue was taken up in 200 ml of water, extracted with methylene chloride, dried on sodium sulfate and the solvent was evaporated. The residue was chromatographed by high performance liquid chromatography (HPLC) (SiO₂ 15-25μ), the elution agent being a mixture of ethyl acetate (60%) and n-heptane (40%), and distillated BP₀.1 =175° C. 70% of product were obtained. [α]_(D) ²⁰ =+44° 3 (C=5, ethanol). Empirical formula: C₁₁ H₁₆ O₃.

Second step: methoxy-3 propane diol-1,2 (S) (XIII)

A solution of 4.44 g of the compound obtained in the first step, in 200 ml of ethanol and 1 drop of hydrochloric ethanol, was hydrogenolised at a pressure of 5 kg and a temperature of 30° C., in the presence of 10% palladium charcoal. Then the mixture was filtered, a few gms. bicarbonate was added to the filtrate, the solvent was evaporated, the residue was taken up in ether, washed with water, dried on sodium sulfate, and the solvent was evaporated. 2.37 g of product were obtained after HPCL (SiO₂) of the crude product, the elution agent being a mixture of ethylacetate (60%) and n-heptane (40%).

Third step: toluene sulfonyloxy-1 hydroxy-2 methoxy-3 propane (R) (XII)

To a solution of 2.37 g of the compound obtained at the preceding step, in 10 ml of pyridine, cooled at 0° C., was slowly added a solution of 4.27 g of tosyl chloride in 50 ml of benzene. Then the mixture was left for 40 hours at room temperature, diluted with ether, filtered and the filtrate was washed with 1 N hydrochloric acid, then with water and with an aqueous solution of sodiim bicarbonate until neutrality. Then it was dried on sodium sulfate and the solvent was evaporated. The residue was chromatographed by HPLC (elution agent: ethyl acetate: 60%; n-heptane 40%). Yield: 53%. The product obtained was directly used in the synthesis of the compound of formula (Ib) according to the method described in the first step of Example 4.

EXAMPLE 6 para benzyloxyphenyl-3 N-methylaminomethyl-5 oxazolidinone-2 (I)

Code number: 81

First step: mesylate of parabenzyloxyphenyl-3 hydroxymethyl-5 oxazolidinone-2 (XV)

To a solution of 28.5 g of para benzyloxyphenyl-3 hydroxymethyl-5 oxazolidinone-2 (IId) in 27 ml of triethylamine and 750 ml of methylene chloride cooled to 5° C., were added 15 ml of mesyl chloride. They were left for 15 minutes in contact, then the solution was concentrated, diluted with water and the precipitate was filtered and recrystallized in acetone. 32 g of product were obtained

    ______________________________________                                         Yield:              90%                                                        Melting point:      163° C.                                             Empirical formula:  C.sub.18 H.sub.19 NO.sub.6 S                               Molecular weight:   377.41                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              57.28       5.07   3.71                                           Found (%)    57.30       4.95   3.46                                           ______________________________________                                    

Second step: para benzyloxyphenyl-3 N-methylaminomethyl-5 oxazolidinone-2 [I]

A mixture of 29 g of the compound obtained at the preceding step and 50 g of ammonia in 500 ml of methanol, was heated to 110° C. for 6 hours in an autoclave. Then the solvent was evaporated, the residue was taken up in chloroform, washed with water, the solvent was evaporated and the residue was recrystallized in isopropanol. 17 g of product were isolated.

    ______________________________________                                         Yield:              74%                                                        Melting point:      124° C.                                             Empirical formula:  C.sub.17 H.sub.18 N.sub.2 O.sub.3                          Molecular weight:   298.33                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              68.44       6.08   9.39                                           Found (%)    68.25       6.19   8.82                                           ______________________________________                                    

By the same method, but from the corresponding reagents, the compounds of formula (I) were prepared, given in table I and bearing the code numbers: 74 to 86; 170 to 176 and 201 to 207.

EXAMPLE 7 N-parabenzyloxyphenyl-1 hydroxymethyl-4 pyrrolidinone-2 (XVII) First step: [(N-parabenzyloxyphenyl pyrrolidione-2) yl-4] carboxylic acid (XIX)

A mixture of 46 g of itaconic acid and 70 g of parabenzyloxyaniline in 400 ml of water was brought to reflux, then washed on the filter with chloroform, dried and recrystallized in acetone. 77 g of product were obtained.

    ______________________________________                                         Yield:               71%                                                       Melting point:       194° C.                                            Empirical formula:   C.sub.18 H.sub.17 NO.sub.4                                Molecular weight:    311.32                                                    Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              69.44       5.50   4.50                                           Found (%)    69.69       5.48   4.80                                           ______________________________________                                    

Second step: [(N-parabenzyloxyphenyl pyrrolidinone-2) yl-4]ethyl carboxylate (XVIII)

A solution of 84 g of the acid obtained in the first step in 400 ml of ethanol and 6 ml of concentrated sulfuric acid was brought to reflux for 2 hours. Then, it was cooled, the precipitate was filtered, washed with water, dried and recrystallized in isopropanol. 47 g of product were obtained.

    ______________________________________                                         Yield:               51%                                                       Melting point:       106° C.                                            Empirical formula:   C.sub.20 H.sub.21 NO.sub.4                                Molecular weight:    339.38                                                    Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              70.78       6.24   4.13                                           Found (%)    70.96       6.39   4.44                                           ______________________________________                                    

Third step: N-para benzyloxyphenyl-1 hydroxymethyl-4 pyrrolidinone-2 (XVII)

To a mixture of 7.9 g of sodium borohydride and 18 g of lithium bromide in 400 ml of diglyme, were added 70 g of the compound prepared at the preceeding step. Then the mixture was brught to 100° C. in 50 mn, diluted in 500 g of ice and 50 ml of concentrated hydrochloric acid, extracted with chloroform; the solvent was evaporated, the residue was crystallized in isopropyl ether and recrystallized in toluene. 45 g of product were obtained.

    ______________________________________                                         Yield:               72%                                                       Melting point:       110° C.                                            Empirical formula:   C.sub.18 H.sub.19 NO.sub.3                                Molecular weight:    297.34                                                    Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              72.70       6.44   4.71                                           Found (%)    72.44       6.36   4.68                                           ______________________________________                                    

EXAMPLE 8 N-parabenzyloxyphenyl hydroxymethyl-3 pyrrolidine (I) Code number: 220

A solution of 53 g of the compound of formula (XVIII) obtained in example 7, in 300 ml of anhydrous tetrahydrofuran, was added while cooling to 11.8 g of lithium aluminum hydride (pellets) in 1000 ml of tetrahydrofuran. Then it was brought to reflux for 2 hours, then 6.3 ml of water, 4.75 ml of 20% NaOH and 22 ml of water were successively added. It was filtered, the filtrate was evaporated and the residue was crystallized in ethyl acetate. 38 g of product were obtained.

    ______________________________________                                         Yield:               85%                                                       Melting point:       87° C.                                             Empirical formula:   C.sub.18 H.sub.21 NO.sub.2                                Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              76.29       7.47   4.94                                           Found (%)    76.40       7.60   4.65                                           ______________________________________                                    

EXAMPLE 9 para (metanitro) benzyloxyphenyl-3 methoxymethyl-5 thiazolidinone-2(I) Code number: 219 First step: para (metanitro) benzyloxyanilino-3 methoxy-1 propane thiol-2, oxalate (XX)

To a solution of 48.8 g of para (metanitro) benzyloxyaniline in 700 ml of isopropanol were slowly added 20.8 g of methoxymethyl-2 thiooxirane, and the mixture was brought to reflux for 7 hours. Then the solvent was evaporated, and the residue was chromatographed on a silica column. By eluting with methylene chloride, 38.4 g of an oil were obtained which were dissolved in acetonitrile. A solution of oxalic acid was added to acetonitrile, and the precipitate was filtered.

    ______________________________________                                         Yield:              43%                                                        Melting point:      120° C.                                             Empirical formula:  C.sub.19 H.sub.22 N.sub.2 O.sub.8 S                        Molecular weight:   438.45                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              52.04       5.06   6.39                                           Found (%)    51.79       4.88   6.48                                           ______________________________________                                    

Second step: para (metanitro) benzyloxyphenyl-3 methoxymethyl-5 thiazolidinone-2 (I) Code number: 219

To a solution of 3 g of phosgene in 90 ml of dichloroethane, cooled to -10° C., was added 4.14 g of potassium carbonate then 6 g of the compound of formula (XX) (base form) obtained in the previous step, dissolved in 50 ml of dichlorethane, while maintaining the temperature between 5° and 10° C. Then, it came slowly to room temperature (3 hours), water was added, the organic phase was decanted, dried on sodium sulfate and the solvent was evaporated. The residue was crystallized in isopropyl ether, and recrystallized in isopropyl alcohol. 3 g of product were obtained.

    ______________________________________                                         Yield:              47%                                                        Melting point:      74° C.                                              Empirical formula:  C.sub.18 H.sub.18 N.sub.2 O.sub.5 S                        Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              57.74       4.85   7.48                                           Found (%)    57.45       4.97   7.18                                           ______________________________________                                    

EXAMPLE 10 para ethoxyphenyl-3 hydroxymethyl-5 oxazolidine thione-2 (I) Code number: 87

To a solution of 9.6 g of paraethoxyanilino-3 propanediol-1,2 (XXI) and 20.5 ml of triethylamine in 100 ml of tetrahydrofuran, were slowly added 5.2 g of thiophosgene while maintaining the temperature to 20° C. Then after 4 hours it was filtered, the filtrate was evaporated and the residue chromatographed on a silica column. Eluted with chloroform, 5.3 g of product were obtained.

    ______________________________________                                         Yield:              46%                                                        Melting point:      133° C.                                             Empirical formula:  C.sub.12 H.sub.15 NO.sub.3 S                               Molecular weight:   253.31                                                     Elementary analysis:                                                           ______________________________________                                                      C           H      N                                              ______________________________________                                         Calculated (%)                                                                              56.89       5.97   5.53                                           Found (%)    56.98       6.14   5.54                                           ______________________________________                                    

By the same method, but from the corresponding reagents, the compounds of formula (I) were prepared, given in table I and bearing code numbers: 88 to 98; 100, 101, 102, 113 to 120; 177 and 208 to 218.

    TABLE I       ##STR70##        Melting  ELEMENTARY ANALYSIS Code  Empirical Molecular point Yield C H N       C H N Number X A R.sub.1 R.sub.2 R formula weight (°C.) (%)      Calculated (%) Obtained (%)        1 Oxygen Oxygen H CH.sub.2 OCOCH.sub.3 4-OCH.sub.2CN C.sub.14 H.sub.14      N.sub.2 O.sub.5 290.27 92 72 57.93 4.86 9.65 57.90 4.87 9.42 2 " " "      CH.sub.2 OCOEt " C.sub.15 H.sub.16 N.sub.2 O.sub.5 304.29 66 81 59.20      5.30 9.21 59.11 5.37 9.06  3 " " " CH.sub.2       OCOCH.sub.3      ##STR71##       " " 68 75 59.20 5.30 9.21 59.03 5.25 9.35  4 " " " CH.sub.2 OCOEt "      C.sub.16 H.sub.18 N.sub.2 O.sub.5 318.32 66 80 60.37 5.70 8.80 60.44      5.54 8.64       5 " " "      ##STR72##       " C.sub.17 H.sub.20 N.sub.2 O.sub.5 332.34 72 58 61.43 6.07 8.43 61.14      6.23 8.37  6 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.18 H.sub.22      N.sub.2 O.sub.5 346.37 65 72 62.41 6.40 8.09 62.70 6.59 7.94  7 " " "       ##STR73##       " C.sub.18 H.sub.22 N.sub.2 O.sub.5 346.37 90 57 62.41 6.40 8.09 62.29      6.21 7.90       8 " " "      ##STR74##       " C.sub.20 H.sub.24 N.sub.2 O.sub.5 372.41 104 76 64.50 6.50 7.52 64.35      6.30 7.69  9 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.22 H.sub.30      N.sub.2 O.sub.5 402.48 75 75 65.65 7.51 6.96 65.41 7.35 6.72  10 " " "       ##STR75##       " C.sub.20 H.sub.18 N.sub.2 O.sub.5 366.36 150 68 65.56 4.95 7.65 65.27      4.82 7.55  11 " " " CH.sub.2 OCOCH.sub.3 4 OC.sub.4 H.sub.94 C.sub.16      H.sub.21 NO.sub.5 307.34 60 92 62.52 6.89 4.56 62.49 6.90 4.55  12 " " "       ##STR76##       " C.sub.19 H.sub.27 NO.sub.5 349.41 82 30 65.31 7.79 4.01 65.04 7.72      3.81  13 " " " CH.sub.2       OCOCH.sub.3      ##STR77##       C.sub.18 H.sub.23 NO.sub.5 333.37 94 85 64.85 6.95 4.20 64.91 7.24 4.05       14 " " " CH.sub.2 OCOEt " C.sub.19 H.sub.25 NO.sub.5 347.39 90 82 65.69      7.25 4.03 65.76 7.20 4.35       15 " " "      ##STR78##       " C.sub.20 H.sub.27 NO.sub.5 361.42 78 54 66.46 7.53 3.88 66.21 7.51      3.66  16 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.21 H.sub.29 NO.sub.5      375.45 82 72 67.18 7.79 3.73 67.24 8.08 3.58       17 " " "      ##STR79##       " C.sub.21 H.sub.29 NO.sub.5 375.45 94 66 67.18 7.79 3.73 67.19 7.92      3.54       18 " " "      ##STR80##       " C.sub.23 H.sub.31 NO.sub.5 401.49 100 71 68.80 7.78 3.49 68.51 7.94      3.19  19 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.25 H.sub.37      NO.sub.5 431.55 78 62 69.57 8.64 3.25 69.76 8.91 3.10       20 " " "      ##STR81##       " C.sub.23 H.sub.25 NO.sub.5 395.44 112 65 69.85 6.37 3.54 69.96 6.64      3.66  21 " " " CH.sub.2       OCOCH.sub.3      ##STR82##       C.sub.19 H.sub.25 NO.sub.5 347.39 102 72 65.69 7.25 4.03 65.96 7.55      3.98  22 " " " CH.sub.2 OCOEt " C.sub.20 H.sub.27 NO.sub.5 361.42 80 80      66.46 7.53 3.88 66.68 7.52 4.13  23 " " " CH.sub.2       OCOCH.sub.3      ##STR83##       C.sub.19 H.sub.19 NO.sub.5 341.35 120 76 66.85 5.61 4.10 67.07 5.54      3.86  24 " " " CH.sub.2 OCOEt " C.sub.20 H.sub.21 NO.sub.5 355.37 96 82      67.59 5.96 3.94 67.60 6.15 3.92       25 " " "      ##STR84##       " C.sub.21 H.sub.23 NO.sub.5 369.40 114 65 68.28 6.28 3.79 68.31 6.40      3.73  26 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.25 NO.sub.5      383.43 86 71 68.91 6.57 3.65 69.02 6.55 3.60       27 " " "      ##STR85##       " C.sub.22 H.sub.25 NO.sub.5 383.43 116 52 68.91 6.57 3.65 69.16 6.63      3.55  28 " " " CH.sub. 2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.33      NO.sub.5 439.53 95 60 71.04 7.57 3.19 70.97 7.52 2.90       29 " " "      ##STR86##       " C.sub.24 H.sub.21 NO.sub.5 403.42 128 69 71.45 5.25 3.47 71.26 5.08      3.15  30 " " " CH.sub.2       OCOCH.sub.3      ##STR87##       C.sub.19 H.sub.18 ClNO.sub.5 375.79 58 85 60.72 4.83 3.73 60.87 4.94      3.62  31 " " " CH.sub.2 OCOEt " C.sub.20 H.sub.20 ClNO.sub.5 389.82 82      82 61.62 5.17 3.59 61.64 5.45 3.59       32 " " "      ##STR88##       " C.sub.21 H.sub.22 ClNO.sub.5 403.85 88 62 62.45 5.49 3.47 62.30 5.46      3.20  33 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.24       ClNO.sub.5 417.88 95 73 63.23 5.79 3.35 63.27 5.69 3.17  34 " " "       ##STR89##       " " " 92 65 63.23 5.79 3.35 63.22 5.67 3.25  35 " " " CH.sub.2       OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.32 ClNO.sub.5 473.98 74 65 65.88      6.81 2.96 66.11 7.05 3.22  36 " " " CH.sub.2       OCOCH.sub.3      ##STR90##       C.sub.19 H.sub.18 N.sub.2 O.sub.7 386.35 126 72 59.06 4.70 7.25 59.10      4.56 6.95  37 Oxygen Oxygen H CH.sub.2 OCOEt " C.sub.20 H.sub.20 N.sub.2      O.sub.7 400.38 106 75 59.99 5.03 7.00 59.86 5.03 6.71       38 " " "      ##STR91##       " C.sub.21 N.sub.22 N.sub.2 O.sub.7 414.40 108 58 60.86 5.35 6.76 60.62      5.45 6.49  39 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.24      N.sub.2 O.sub.7 428.43 102 70 61.67 5.65 6.54 61.75 5.69 6.39  40 " " "       ##STR92##       " C.sub.22 H.sub.24 N.sub.2 O.sub.7 428.43 118 43 61.67 5.65 6.54 61.41      5.88 6.35       41 " " "      ##STR93##       " C.sub.24 H.sub.26 N.sub.2 O.sub.7 454.46 150 28 63.42 5.77 6.16 63.54      5.83 5.89  42 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.32      N.sub.2 O.sub.7 484.53 83 65 64.45 6.66 5.78 64.18 6.82 5.64  43 " " "       ##STR94##       " C.sub.24 H.sub.20 N.sub.2 O.sub.7 448.42 182 60 64.28 4.50 6.25 64.39      4.39 6.17  44 " " " CH.sub.2       OCOEt      ##STR95##       C.sub.20 H.sub.20 FNO.sub.5 373.39 77 70 64.33 5.40 3.75 64.28 5.27      3.73  45 " " " CH.sub.2 OCH.sub.3 3-CH.sub.3 C.sub.12 H.sub.15 NO.sub.3      221.25 58 71 65.14 6.83 6.33 65.36 6.66 6.01 46 " " " " 4 OC.sub.4      H.sub.9 n C.sub.15 H.sub.21 NO.sub.4 279.33 50 57 64.49 7.58 5.01 64.40      7.55 4.79       47 " " "      ##STR96##       " C.sub.17 H.sub.25 NO.sub.4 307.38 77 62 66.42 8.20 4.56 66.19 8.27      4.36       48 " " "      ##STR97##       " C.sub.20 H.sub.29 NO.sub.4 347.44 53 71 69.13 8.41 4.03 69.30 8.62      3.83  49 " " " CH.sub.2       OCH.sub.3      ##STR98##       C.sub.17 H.sub.23 NO.sub.4 305.36 70 48 66.86 7.59 4.59 66.79 7.47 4.44       50 " " "      ##STR99##       " C.sub.19 H.sub.27 NO.sub.4 333.41 66 35 68.44 8.16 4.20 68.54 8.39      4.22       51 " " "      ##STR100##       " C.sub.22 H.sub.31 NO.sub.4 373.47 67 59 70.75 8.37 3.75 70.63 8.53      3.85  52 " " " CH.sub.2       OCH.sub.3      ##STR101##       C.sub.14 H.sub.16 N.sub.2 O.sub.4 276.28 104 57 60.86 5.84 10.14 60.59      5.50 10.11       53 " " "      ##STR102##       " C.sub.16 H.sub.20 N.sub.2 O.sub.4 304.34 89 39 63.14 6.62 9.21 63.29      6.73 9.36       54 " " "      ##STR103##       " C.sub.19 H.sub.24 N.sub.2 O.sub.4 344.39 80 42 66.26 7.02 8.13 66.19      6.88 7.98  55 " " " CH.sub.2       OCH.sub.3      ##STR104##       C.sub.18 H.sub.25 NO.sub.4 319.39 90 63 67.69 7.89 4.39 67.96 7.83 4.39       56 " " " "      ##STR105##       C.sub.18 H.sub.23 NO.sub.4 317.37 80 55 68.12 7.30 4.41 68.21 7.61 4.39       57 Oxygen Oxygen H CH.sub.2       OCH.sub.3      ##STR106##       C.sub.18 H.sub.19 NO.sub.4 313.34 90 83 68.99 6.11 4.47 69.19 6.07 4.24       58 " " "      ##STR107##       " C.sub.20 H.sub.23 NO.sub.4 341.39 110 75 70.36 6.79 4.10 70.14 6.49      4.22  59 " " " CH.sub.2       OCH.sub.3      ##STR108##       C.sub.18 H.sub.18 ClNO.sub.4 347.79 96 78 62.16 5.22 4.03 61.99 5.11      3.88       60 " " "      ##STR109##       " C.sub.20 H.sub.22 ClNO.sub.4 375.84 99 70 63.91 5.90 3.73 63.92 5.90      3.68  61 " " " CH.sub.2       OCH.sub.3      ##STR110##       C.sub.18 H.sub.18 N.sub.2 O.sub.6 358.34 78 62 60.33 5.06 7.82 60.52      5.10 7.92       62 " " "      ##STR111##       " C.sub.20 H.sub.22 N.sub.2 O.sub.6 386.39 74 60 62.16 5.74 7.25 62.16      5.94 7.49       63 " " "      ##STR112##       " C.sub.23 H.sub.26 N.sub.2 O.sub.6 426.45 78 60 64.77 6.15 6.57 64.51      6.18 6.50  64 " " " CH.sub.2       OCH.sub.3      ##STR113##       C.sub.18 H.sub.18 FNO.sub.4 331.33 106 55 65.25 5.48 4.23 65.37 5.52      4.20       65 " " " "      ##STR114##       C.sub.19 H.sub.18 N.sub.2 O.sub.4 338.35 88 65 67.44 5.36 8.28 67.41      5.48 8.37       66 " " " "      ##STR115##       C.sub.19 H.sub.18 F.sub.3 NO.sub.4 381.34 83 60 59.84 4.76 3.67 59.81      4.62 3.70       67 " " " "      ##STR116##       C.sub.18 H.sub.18 FNO.sub.4 331.33 79 60 65.25 5.48 4.23 65.20 5.59      4.13       68 " " " "      ##STR117##       C.sub.18 H.sub.18 ClNO.sub.4 347.79 107 65 62.16 5.22 4.03 62.02 5.23      4.05  69 " " " CH.sub.2       OEt      ##STR118##       C.sub.19 H.sub.20 N.sub.2 O.sub.6 372.37 50 48 61.28 5.41 7.52 61.10      5.34 7.48  70 " " " CH.sub.2 OC.sub.3 H.sub.7n " C.sub.20 H.sub.22      N.sub.2 O.sub.6 386.39 52 75 62.16 5.74 7.25 62.09 5.63 7.06 71 " " "       ##STR119##       " C.sub.20 H.sub.20 N.sub.2 O.sub.6 384.38 <50 40 62.49 5.24 7.29 62.38      5.12 7.17       72 " " "      ##STR120##       " C.sub.20 H.sub.18 H.sub.2 O.sub.6 382.36 80 55 62.82 4.75 7.33 62.75      4.76 7.23       73 " " "      ##STR121##       " C.sub.19 H.sub.20 N.sub.2 O.sub.7 388.37 79 50 58.76 5.19 7.21 58.53      5.26 7.20  74 " " " CH.sub.2NHCH.sub.3 4 OC.sub.4 H.sub.9n C.sub.15      H.sub.22 N.sub.2 O.sub.3 278.34 56 75 64.72 7.97 10.07 64.57 7.81 10.18      75 " " "       ##STR122##       " C.sub.16 H.sub.24 N.sub.2 O.sub.3 292.37 68 70 65.73 8.27 9.58 65.73      8.01 9.49       76 " " " CH.sub.2NH.sub.2      ##STR123##       C.sub.16 H.sub.22 N.sub.2 O.sub.3 290.35 97 72 66.18 7.64 9.65 66.33      7.96 9.79  77 " " " CH.sub.2NHCH.sub.3 " C.sub.17 H.sub.24 N.sub.2      O.sub.3 304.38 71 70 67.08 7.95 9.20 66.85 7.96 9.14       78 " " "      ##STR124##       " C.sub.18 H.sub.26 N.sub.2 O.sub.3 318.40 102 65 67.89 8.23 8.80 67.88      8.43 8.73 79 " " " CH.sub.2NHCH.sub.3       ##STR125##       C.sub.16 H.sub.24 N.sub.2 O.sub.3 292.37 67 62 65.73 8.27 9.58 65.44      8.23 9.73       80 " " " CH.sub.2NH.sub.2      ##STR126##       C.sub.17 H.sub.18 N.sub.2 O.sub.3 298.33 124 74 68.44 6.08 9.39 68.25      6.19 8.82   81 " " " CH.sub.2NHCH.sub.3 " C.sub.18 H.sub.20 N.sub.2      O.sub.3 312.36 88 71 69.21 6.45 8.97 69.51 6.36 8.42 82 " " " CH.sub.2NH.      sub.2       ##STR127##       C.sub.17 H.sub.17 ClN.sub.2 O.sub.3 332.78 122 70 61.35 5.15 8.42 61.04      5.20 7.66  83 " " " CH.sub.2NHCH.sub.3 " C.sub.18 H.sub.19 ClN.sub.2      O.sub.3 346.81 72 55 62.33 5.52 8.08 61.93 5.35 8.35       84 " " " CH.sub.2NH.sub.2       ##STR128##       C.sub.17 H.sub.17 N.sub.3 O.sub.5 343.33 88 50 59.47 4.99 12.24 59.21      4.71 12.54  85 " " " CH.sub.2NHCH.sub.3 " C.sub.18 H.sub.19 N.sub.3      O.sub.5 357.36 70 75 60.49 5.36 11.76 60.18 5.39 11.83  86 " " "       ##STR129##       " C.sub.19 H.sub.21 N.sub.3 O.sub.5 371.38 76 72 61.44 5.70 11.32 61.54      5.84 11.29  87 Sulfur " " CH.sub.2 OH 4-OEt C.sub.12 H.sub.15 NO.sub.3 S      253.31 133 46 56.89 5.97 5.53 56.98 6.14 5.54  88 " " " " 4 OC.sub.3      H.sub.7n C.sub.13 H.sub.17 NO.sub.3 S 267.34 84 42 58.40 6.41 5.24 58.55      6.59 5.25  89 " " " " 4 OC.sub.4 H.sub.9n C.sub.14 H.sub.19 NO.sub.3 S      281.37 95 55 59.76 6.81 4.98 59.64 6.80 4.86       90 " " " "      ##STR130##       C.sub.17 H.sub.23 NO.sub.3 S 321.43 100 40 63.52 7.21 4.36 63.27 7.01      4.15       91 " " " "      ##STR131##       C.sub.15 H.sub.21 NO.sub.3 S 295.39 80 40 60.99 7.17 4.74 60.75 7.10      4.74       92 " " " "      ##STR132##       C.sub.12 H.sub.11 N.sub.2 O.sub.3 S 263.29 96 35 54.74 4.21 10.64 54.49      4.64 10.70       93 "  " " "      ##STR133##       C.sub.17 H.sub.16 ClNO.sub.3 S 349.83 132 40 58.36 4.61 4.00 58.17 4.61      4.00       94 " " " CH.sub.2OH      ##STR134##       C.sub.17 H.sub.16 N.sub.2 O.sub.3 S 360.38 142 37 56.65 4.48 7.77 56.36      4.29 7.58       95 " " " "      ##STR135##       C.sub.17 H.sub.16 ClNO.sub.3 S 349.83 163 42 58.36 4.61 4.00 58.31 4.55      3.98       96 " " " "      ##STR136##       C.sub.17 H.sub.16 FNO.sub.3 S 333.37 142 55 61.24 4.84 4.20 60.99 4.83      3.92       177 " " " "      ##STR137##       " " 153 37 61.24 4.84 4.20 60.94 4.78 4.10       97 " " " "      ##STR138##       C.sub.18 H.sub. 16 N.sub.2 O.sub.3 S 340.39 162 40 63.51 4.74 8.23      63.30 5.00 8.08       98 " " " "      ##STR139##       C.sub.18 H.sub.16 F.sub.3 NO.sub.3 S 383.38 95 52 56.39 4.21 3.65 56.08      4.14 3.30       99 Oxygen CH.sub.2 H "      ##STR140##       C.sub.18 H.sub.18 N.sub.2 O.sub.5 342.34 96 85 63.15 5.30 8.18 62.98      5.31 7.96       100 Sulfur Oxygen H "      ##STR141##       C.sub.16 H.sub.21 NO.sub.3 S 307.40 63 40 62.51 6.89 4.56 62.33 6.90      4.56       101 " " " "      ##STR142##       C.sub.17 H.sub.21 NO.sub.3 S 319.41 112 35 63.92 6.63 4.39 63.64 6.76      4.17       102 " " " "      ##STR143##       C.sub.13 H.sub.14 N.sub.2 O.sub.3 S 278.32 108 43 56.10 5.07 10.07      55.80 5.05 9.87       103 Oxygen " "      ##STR144##       ##STR145##       C.sub.21 H.sub.29 NO.sub.5 375.45 98 76 67.18 7.79 3.73 67.45 7.87 3.97       104 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.31 NO.sub.5      389.47 96 76 67.81 8.02 3.60 67.91 8.01 3.54       105 " " "      ##STR146##       " C.sub.22 H.sub.31 NO.sub.5 389.47 120 73 67.84 8.02 3.60 67.86 8.10      3.45  106 " " " CH.sub.2       OCOEt      ##STR147##       C.sub.20 H.sub.20 FNO.sub.5 373.37 77 80 64.33 5.40 3.75 64.28 5.27      3.73       107 " " "      ##STR148##       " C.sub.21 H.sub.22 FNO.sub.5 387.39 87 62 65.10 5.72 3.62 65.19 5.78      3.60  108 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.22 H.sub.24      FNO.sub.5 401.42 92 71 65.82 6.03 3.49 65.83 5.86 3.42  109 " " "      CH.sub.2 OEt 4-OC.sub.4 H.sub.9 n C.sub.16 H.sub.23 NO.sub.4 293.35 64      32 65.50 7.90 4.78 65.63 8.08 4.67  110 " " " CH.sub.2 OCH.sub.3       ##STR149##       C.sub.15 H.sub.18 N.sub.2 O.sub.4 290.31 54 68 62.05 6.25 9.65 62.07      6.42 9.61       111 " " " "      ##STR150##       C.sub.16 H.sub.23 NO.sub.4 293.35 50 65 65.50 7.90 4.78 65.52 8.03 4.71       112 O O H CH.sub.2 OCH.sub.3 4-O(CH.sub.2).sub.4CN C.sub.16 H.sub.20      N.sub.2 O.sub.4 304.34 78 50 63.14 6.62 9.21 63.00 6.45 9.09  113 Sulfur      Oxygen " CH.sub.2       OH      ##STR151##       C.sub.17 H.sub.15 NClO.sub.5 S 394.83 144 58 51.71 3.83 7.10 51.87 3.87      7.34  114 " " " CH.sub.2       OCH.sub.3      ##STR152##       C.sub.18 H.sub.25 NO.sub.3 S 335.45 102 76 64.44 7.51 4.18 64.35 7.46      4.12  115 " " " CH.sub.2 OCOCH.sub.3 " C.sub.19 H.sub.25 NO.sub.4 S      363.46 96 52 62.78 6.93 3.85 62.64 7.00 3.85  116 " " " CH.sub.2      OCH.sub.3       ##STR153##       C.sub.19 H.sub.18 N.sub.2 O.sub.3 S 354.42 108 61 64.38 5.12 7.90 64.37      4.82 7.76 117 " " " CH.sub.2       OCOCH.sub.3      ##STR154##       C.sub.19 H.sub.18 N.sub.2 O.sub.6 S 402.42 104 71 56.71 4.51 6.96 56.91      4.28 6.73  118 " " " CH.sub.2 OCH.sub.3 " C.sub.18 H.sub.18 N.sub.2      O.sub.5 S 374.41 97 67 57.74 4.85 7.48 57.60 4.77 7.40  119 " " "      CH.sub.2       OH      ##STR155##       C.sub.16 H.sub.21 NO.sub.4 S 323.40 117 58 59.42 6.55 4.33 59.17 6.62      4.26  120 " " " CH.sub.2       OCOCH.sub.3      ##STR156##       C.sub.20 H.sub.18 N.sub.2 O.sub.4 S 382.43 99 82 62.81 4.74 7.33 62.88      4.67 7.33       121 Oxygen " "      ##STR157##       ##STR158##       C.sub.24 H.sub.33 NO.sub.5 415.51 128 87 69.37 8.01 3.37 69.33 7.99      3.29  122 " " " CH.sub.2 OCOC.sub.8       H.sub.17n      ##STR159##       C.sub.26 H.sub.39 NO.sub.5 445.58 82 78 70.08 8.82 3.14 70.01 8.67 3.06       123 " " " CH.sub.2       OCOCH.sub.3      ##STR160##       C.sub.17 H.sub.23 NO.sub.5 321.36 80 60 63.53 7.21 4.36 63.66 7.36 4.39       124 " " " CH.sub.2 OCOEt " C.sub.18 H.sub.25 NO.sub.5 335.39 78 60      64.46 7.51 4.18 64.35 6.96 4.25       125 " " "      ##STR161##       " C.sub.20 H.sub.29 NO.sub.5 363.24 75 74 66.09 8.04 3.85 65.91 7.73      3.80  126 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.24 H.sub.37      NO.sub.5 419.54 67 72 68.70 8.89 3.34 68.41 8.93 3.19  127 " " "       ##STR162##       ##STR163##       C.sub.19 H.sub.27 NO.sub.5 349.41 64 76 65.31 7.79 4.01 65.24 7.88 3.98       128 " " " CH.sub.2 OCOC.sub.4 H.sub.9n " C.sub.20 H.sub.29 NO.sub.5      363.44 70 64 66.09 8.04 3.85 65.96 7.85 3.70       129 " " "      ##STR164##       " C.sub.22 H.sub.31 NO.sub.5 389.48 81 68 67.84 8.02 3.60 67.66 8.03      3.71  130 " " " CH.sub.2       OCOCH.sub.3      ##STR165##       C.sub.19 H.sub.18 FNO.sub.5 359.34 60 65 63.50 5.04 3.89 63.28 5.14      3.70  131 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.32      FNO.sub.5 457.52 73 73 68.24 7.05 3.06 68.30 6.96 3.16  132 " " "      CH.sub.2       OCOEt      ##STR166##       C.sub.21 H.sub.20 N.sub.2 O.sub.5 380.39 90 78 66.30 5.30 7.36 66.31      5.52 7.24  133 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.27 H.sub.32      N.sub.2 O.sub.5 464.54 72 77 69.80 6.94 6.03 69.63 7.15 5.91  134 " " "       ##STR167##       ##STR168##       C.sub.22 H.sub.24 N.sub.2 O.sub.7 428.43 84 40 61.67 5.65 6.54 61.31      5.50 6.28  135 " " " CH.sub.2       OCOEt      ##STR169##       C.sub.20 H.sub.20 FNO.sub.5 373.37 87 81 64.33 5.40 3.75 64.51 5.12      3.70  136 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.32      FNO.sub.5 457.52 94 83 68.25 7.05 3.06 68.54 6.82 2.97  137 " " "      CH.sub.2       OCOEt      ##STR170##       C.sub.20 H.sub.19 ClN.sub.2 O.sub.7 434.82 104 73 55.24 4.40 6.44 54.93      4.11 6.35  138 " " " CH.sub.2 OCOC.sub.8 H.sub.17n " C.sub.26 H.sub.31      ClN.sub.2 O.sub.7 518.99 102 87 60.17 6.02 5.40 60.02 5.82 5.35  139 " "      " CH.sub.2 OCOC.sub.8       H.sub.17n      ##STR171##       C.sub.27 H.sub.31 N.sub.3 O.sub.7 509.54 100 70 63.64 6.13 8.25 63.51      5.99 8.24  140 " " " CH.sub.2 OCOEt " C.sub.21 H.sub.19 N.sub.3 O.sub.7      425.39 145 50 59.29 4.50 9.88 58.67 4.33 9.78  141 " " " CH.sub.2      OCOCH.sub.2       OCH.sub.3      ##STR172##       C.sub.20 H.sub.20 N.sub.2 O.sub.8 416.38 125 55 57.69 4.84 6.73 57.63      4.78 6.58  142 " " " CH.sub.2 OC.sub.3 H.sub.7n 4 OC.sub.4 H.sub.9n      C.sub.17 H.sub.25 NO.sub.4 307.38 72 52 66.42 8.20 4.56 66.35 8.39 4.72      143 " " " "       ##STR173##       C.sub.19 H.sub.27 NO.sub.4 333.41 72 63 68.44 8.16 4.20 68.20 7.89 4.11       144 " " " CH.sub.2       OCH.sub.3      ##STR174##       C.sub.17 H.sub.23 NO.sub.5 321.36 100 81 63.53 7.21 4.36 63.36 7.09      4.27  145 " " " CH.sub.2 OC.sub.3       H.sub.7      ##STR175##       C.sub.16 H.sub.20 N.sub.2 O.sub.4 304.34 40 38 63.14 6.62 9.21 62.96      6.31 8.96  146 " " " CH.sub.2       OEt      ##STR176##       C.sub.18 H.sub.25 NO.sub.4 319.39 82 79 67.69 7.89 4.39 67.44 7.95 4.36      147 " " " CH.sub.2       OEt      ##STR177##       C.sub.15 H.sub.18 N.sub.2 O.sub.4 290.31 77 41 62.05 6.25 9.65 62.15      5.97 9.61  148 " " " CH.sub.2 OCH.sub.3 4 OC.sub.5 H.sub.11n C.sub. 16      H.sub.23 NO.sub.4 293.35 58 82 65.50 7.90 4.78 65.45 7.91 4.68  149 " "      " " 4 OC.sub.6 H.sub.13n C.sub.17 H.sub.25 NO.sub.4 307.38 ≦50 76      66.42 8.20 4.56 66.43 8.12 4.44       150 " " " "      ##STR178##       C.sub.19 H.sub.27 NO.sub.4 333.41 71 32 68.44 8.16 4.20 68.35 8.17 4.37       151 " " " "      ##STR179##       C.sub.14 H.sub.17 NO.sub.5 279.28 58 85 60.20 6.14 5.02 59.94 6.02 5.11       152 " " " CH.sub.2 OC.sub.3       H.sub.7n      ##STR180##       C.sub.20 H.sub.23 NO.sub.4 341.39 105 67 70.36 6.79 4.10 70.17 6.80      3.86       153 " " " "      ##STR181##       C.sub.20 H.sub.22 ClNO.sub.4 375.84 75 71 63.91 5.90 3.73 63.95 6.07      3.93  154 " " " CH.sub.2       OEt      ##STR182##       C.sub.19 H.sub. 21 NO.sub.4 327.37 105 85 69.70 6.47 4.28 69.44 6.48      4.23       155 " " " "      ##STR183##       C.sub.19 H.sub.20 ClNO.sub.4 361.81 81 82 63.07 5.57 3.87 62.89 5.38      3.80  156 " " " CH.sub.2       OCH.sub.3      ##STR184##       C.sub.18 H.sub.17 ClN.sub.2 O.sub.6 392.79 110 64 55.04 4.36 7.13 54.98      4.35 7.17       157 " " "      ##STR185##       ##STR186##       C.sub.21 H.sub.24 N.sub.2 O.sub.6 400.42 76 62 62.99 6.04 7.00 62.68      5.79 6.85       158 " " "      ##STR187##       " C.sub.22 H.sub.26 N.sub.2 O.sub.6 414.44 70 59 63.75 6.32 6.76 63.49      6.11 6.62  159 " " " CH.sub.2       OCH.sub.3      ##STR188##       C.sub.19 H.sub.18 N.sub.2 O.sub.4 338.35 110 78 67.44 5.36 8.28 67.21      5.06 8.20  160 " " " CH.sub.2 OC.sub.3       H.sub.7n      ##STR189##       C.sub.21 H.sub.22 N.sub.2 O.sub.4 366.40 75 60 68.83 6.05 7.65 68.51      5.98 7.67  161 " " " CH.sub.2       OCH.sub.3      ##STR190##       C.sub.19 H.sub.17 N.sub.3 O.sub.6 383.35 163 52 59.63 4.47 10.96 59.50      4.60 10.85       162 " " " "      ##STR191##       C.sub.19 H.sub.17 FN.sub.2 O.sub.4 356.34 93 58 64.04 4.81 7.86 63.78      4.80 7.71       163 " " " "      ##STR192##       C.sub.18 H.sub.17 ClFNO.sub.4 365.78 90 34 59.10 4.68 3.83 59.40 4.55      4.07       164 " " " "      ##STR193##       C.sub.18 H.sub.17 Cl.sub.2 NO.sub.4 382.24 93 83 56.56 4.48 3.66 56.45      4.23 3.66       165 " " " "      ##STR194##       C.sub.18 H.sub.18 N.sub.2 O.sub.6 358.34 134 75 60.33 5.06 7.82 60.08      4.74 7.55       166 " " " "      ##STR195##       C.sub.18 H.sub.17 Cl.sub.2 NO.sub.4 382.24 76 69 56.56 4.48 3.66 56.47      4.46 3.73  167 " " " CH.sub.2       OEt      ##STR196##       C.sub.20 N.sub.20 N.sub.2 O.sub.4 352.38 ≦50 57 68.17 5.72 7.95      67.93 5.50 8.04  168 " " " CH.sub.2       OCH.sub.3      ##STR197##       C.sub.18 H.sub.17 ClN.sub.2 O.sub.6 392.79 94 67 55.04 4.36 7.13 55.04      4.25 7.40       169 " " " "      ##STR198##       C.sub.18 H.sub.17 FN.sub.2 O.sub.6 376.33 95 61 57.44 4.55 7.44 57.30      4.56 7.29  170 " " " CH.sub.2 NH.sub.2 4 OC.sub.4 H.sub.9n C.sub.14      H.sub.20 N.sub.2 O.sub.3 264.32 90 26 63.61 7.63 10.60 63.31 7.47 10.60      171 " " "       ##STR199##       ##STR200##       C.sub.15 H.sub.19 N.sub.3 O.sub.3 289.33 97 17 62.26 6.62 14.52 62.43      6.52 14.46  172 " " " CH.sub.2       NH.sub.2      ##STR201##       C.sub.17 H.sub.24 N.sub.2 O.sub.3 304.38 98 43 67.08 7.95 9.20 67.15      7.87 8.92  173 " " " CH.sub.2 NHCH.sub.3 " C.sub.18 H.sub.26 N.sub.2      O.sub.3 318.40 96 32 67.89 8.23 8.30 68.29 8.17 3.30  174 " " " CH.sub.2      NH.sub.2       ##STR202##       C.sub.15 H.sub.22 N.sub.2 O.sub.3 278.34 84 45 64.72 7.97 10.07 64.80      7.91 10.16  175 " " " CH.sub.2       NHCH.sub.3      ##STR203##       C.sub.18 H.sub.19 N.sub.2 O.sub.3 F 330.35 85 36 65.44 5.80 8.40 65.45      5.82 8.34  176 " " " CH.sub.2 NH.sub.2 " C.sub.17 H.sub.17 N.sub.2      O.sub.2 F 316.32 129 29 44.54 5.42 8.86 64.29 5.46 8.65  178 O O "       ##STR204##       ##STR205##       C.sub.25 H.sub.22 N.sub.2 O.sub.8 478.44 120 64 62.76 4.64 5.86 62.89      4.66 5.84  179 " " " CH.sub.2       OCH.sub.3      ##STR206##       C.sub.15 H.sub.19 NO.sub.4 277.31 63 74 64.96 6.91 5.05 64.67 6.77 4.97       180 " " " "      ##STR207##       C.sub.13 H.sub.18 N.sub.2 O.sub.3 250.29 92 59 62.38 7.25 11.19 62.45      6.98 10.94       181 " " " "      ##STR208##       C.sub.17 H.sub.24 N.sub.2 O.sub.5 336.38 92 75 60.70 7.19 8.33 60.47      7.04 8.10       182 " " " "      ##STR209##       C.sub.17 H.sub.23 NO.sub.5 321.36 77 22 63.53 7.21 4.36 63.67 7.23 4.38       183 " " " "      ##STR210##       C.sub.16 H.sub.21 NO.sub.4 291.34 81 31 65.96 7.27 4.81 66.00 7.46 4.71       184 " " " "      ##STR211##       C.sub.17 H.sub.21 NO.sub.4 303.35 83 33 67.31 6.98 4.62 67.01 7.08 4.43       185 " " " "      ##STR212##       C.sub.16 H.sub.21 NO.sub.4 291.34 84 78 65.96 7.27 4.81 66.03 7.28 4.29       234 " " "  " 4 O(CH.sub.2).sub.4 Cl C.sub.15 H.sub.20 ClNO.sub.4 313.77      58 66 57.41 6.42 4.46 57.05 6.50 4.50       186 " " " "      ##STR213##       C.sub.18 H.sub.25 NO.sub.4 319.39 77 22 67.69 7.89 9.39 67.62 8.03 4.25       187 " " " "      ##STR214##       C.sub.19 H.sub.19 NO.sub.3 309.35 166 26 73.76 6.19 4.53 73.52 6.10      4.38  188 " " " CH.sub.2       OCH.sub.3      ##STR215##       C.sub.18 H.sub.23 NO.sub.5 333.37 102 70 64.85 6.95 4.20 64.82 7.11      4.19       189 " " " "      ##STR216##       C.sub.19 H.sub.17 NO.sub.3 307.33 120 50 74.25 5.58 4.56 74.18 5.30      4.47       190 " " " "      ##STR217##       C.sub.19 H.sub.18 NO.sub.3 Cl 343.80 136 30 66.37 5.28 4.07 66.08 5.24      3.90       191 " " " "      ##STR218##       C.sub.19 N.sub.18 N.sub.2 O.sub.5 354.35 110 50 64.40 5.12 7.91 64.17      5.24 7.96        192 " " " "      ##STR219##       C.sub.19 H.sub.21 NO.sub.3 311.37 74 62 73.29 6.80 4.50 73.17 6.93 4.53       193 " " " "      ##STR220##       C.sub.19 H.sub.19 NO.sub.3 309.35 82 60 73.16 6.19 4.63 73.47 6.10 4.50       194 " " " "      ##STR221##       C.sub.19 H.sub.18 N.sub.2 O.sub.5 354.35 Oil 40 64.40 5.12 7.91 64.25      5.27 7.92       195 " " " "      ##STR222##       C.sub.17 H.sub.17 NO.sub.3 283.31 120 75 72.06 6.05 4.94 72.27 5.91      4.62       196 " " " "      ##STR223##       C.sub.20 H.sub.18 N.sub.2 O.sub.3 334.36 127 70 71.84 5.43 8.38 71.89      5.36 8.45       197 " " " "      ##STR224##       C.sub.18 H.sub.18 BrNO.sub.4 392.24 116 81 55.11 4.63 3.57 54.94 4.35      3.55       198 " " " "      ##STR225##       C.sub.18 H.sub.18 NIO.sub.4 439.24 118 78 49.22 4.13 3.19 49.39 4.08      3.13       199 " " " "      ##STR226##       C.sub.19 H.sub.18 N.sub.2 O.sub.4[α].sub.D.sup.20  = -39°      7 338.35(C = 1/CH.sub.2 Cl.sub.2) 83 75 67.44 5.36 8.28 67.14 5.53 8.38      200 " " " "       ##STR227##       C.sub.19 H.sub.18 N.sub.2 O.sub.4[α].sub.D.sup.20  = +32°      1 338.35(C = 1/CH.sub.2 Cl.sub.2) 84 51 67.44 5.36 8.28 67.52 5.36 8.28      201 " " "       ##STR228##       ##STR229##       C.sub.20 H.sub.23 N.sub.3 O.sub.5 385.41 76 36 62.32 6.02 10.90 62.04      5.90 10.75       202 " " "      ##STR230##       " C.sub.21 H.sub.23 N.sub.3 O.sub.6 413.42 138 26 61.01 5.61 10.17      61.11 5.67 10.01  203 " " " CH.sub.2NHEt " C.sub.19 H.sub.21 N.sub.3      O.sub.5 371.38 70 54 61.44 5.70 11.32 61.48 5.58 11.57  204 " " "       ##STR231##       " C.sub.21 H.sub.23 N.sub.3 O.sub.5 397.42 110 24 63.46 5.83 10.57      63.16 5.90 10.39       205 " " " CH.sub.2NH.sub.2      ##STR232##       C.sub.18 H.sub.17 N.sub.3 O.sub.3 323.34 94 10 66.86 5.30 13.00 66.73      5.58 12.69       206 " " "      ##STR233##       " C.sub.20 H.sub.21 N.sub.3 O.sub.3 351.39 84 62 68.36 6.02 11.96 68.38      6.30 11.68       207 " " " CH.sub.2NH.sub.2      ##STR234##       C.sub.17 H.sub.16 ClN.sub.3 O.sub.5 475.06 155 11 54.04 4.27 11.12      54.17 4.31 11.26  208 S " " CH.sub.2       OCO Et      ##STR235##       C.sub.20 H.sub.20 N.sub.2 O.sub.6 S 416.44 126 73 57.68 4.84 6.73 57.59      5.03 6.69   209 " " " CH.sub.2       OH      ##STR236##       C.sub.18 H.sub.15 FN.sub.2 O.sub.3 S 358.38 126 27 59.57 4.31 7.72      59.72 4.52 7.54  210 " " " CH.sub.2 OC.sub.3       H.sub.7n      ##STR237##       C.sub.20 H.sub.22 N.sub.2 O.sub.5 S 402.46 110 57 59.68 5.51 6.96 59.57      5.65 7.19  211 " " " CH.sub.2       OCH.sub.3      ##STR238##       C.sub.17 H.sub.23 NO.sub.3 S 321.43 68 35 63.52 7.21 4.36 63.61 7.43      4.33  212 " " " CH.sub.2 OH 4 O(CH.sub.2).sub.3CN C.sub.14 H.sub.16      N.sub.2 O.sub.3 S 292.35 80 54 57.51 5.52 9.58 57.40 5.32 9.42  213 " "      " CH.sub.2       OCH.sub.3      ##STR239##       C.sub.17 H.sub.18 N.sub.2 O.sub.3 S 460.95 133 17 51.85 4.57 6.08 51.68      4.40 6.04       214 " " " "      ##STR240##       C.sub.16 H.sub.33 NO.sub.3 S 309.42 Oil 30 62.10 7.49 4.53 62.41 7.61      4.45  215 " " " CH.sub.2 OH 4 O(CH.sub.2).sub.4CN C.sub.15 H.sub.18      N.sub.2 O.sub.3 S 306.37 106 40 58.80 5.92 9.14 58.88 5.74 9.12  216 " "      " CH.sub.2       O Et      ##STR241##       C.sub.19 H.sub.20 N.sub.2 O.sub.5 S 388.43 80 47 58.75 5.19 7.21 58.68      5.09 7.28  217 " " " CH.sub.2 O CH.sub.3 4 O(CH.sub.2).sub.4CN C.sub.16      H.sub.20 N.sub.2 O.sub.3 S 320.40 Oil 24 59.97 6.29 8.74 59.81 6.28 9.02       218 " " " "      ##STR242##       C.sub.19 H.sub.17 N.sub.3 O.sub.5 S 399.42 176 57 57.13 4.29 10.52      57.06 4.19 10.46       219 O S " "      ##STR243##       C.sub.18 H.sub.18 N.sub.2 O.sub.5 S 374.41 74 47 57.74 4.85 7.48 57.45      4.97 7.18  220 H.sub.2 CH.sub.2 " CH.sub.2       OH      ##STR244##       C.sub.18 H.sub.21 NO.sub.2 283.36 87 85 76.29 7.47 4.94 76.40 7.60      4.65

                                      TABLE II                                     __________________________________________________________________________      ##STR245##                                                                                              Melting                                              Code          Empirical                                                                            Molecular                                                                            Point                                                                               Yield                                                                              Elementary Analysis                         Number                                                                              R.sub.6  Formula                                                                              Weight                                                                               (°C.)                                                                        %   %  C  H  N                                  __________________________________________________________________________     226  C.sub.3 H.sub.7n                                                                        C.sub.20 H.sub.23 NO.sub.4                                                           341.39                                                                               105  62  Cal.                                                                              70.36                                                                             6.79                                                                              4.10                                                                  Obt.                                                                              70.17                                                                             6.80                                                                              3.86                               227  Et       C.sub.19 H.sub.21 NO.sub.4                                                           327.37                                                                               105  58  Cal.                                                                              69.70                                                                             6.47                                                                              4.28                                                                  Obt.                                                                              69.44                                                                             6.48                                                                              4.23                               228                                                                                  ##STR246##                                                                             C.sub.21 H.sub.25 NO.sub.4                                                           355.42                                                                               107  61  Cal. Obt.                                                                         70.96 71.09                                                                       7.09 6.77                                                                         3.94 3.70                          229                                                                                  ##STR247##                                                                             C.sub.22 H.sub.27 NO.sub.4                                                           369.44                                                                               101  61  Cal. Obt.                                                                         71.52 71.71                                                                       7.37 7.41                                                                         3.79 3.83                          __________________________________________________________________________

                                      TABLE III                                    __________________________________________________________________________      ##STR248##                                           (VIII)                                                        Melting  ELEMENTARY                                                            Point                                                                               Yield                                                                              ANALYSIS                         Code Number                                                                            R'.sub.6  Empirical Formula                                                                        Molecular Weight                                                                        (°C.)                                                                        (%)    C  H  N                       __________________________________________________________________________     221                                                                                     ##STR249##                                                                              C.sub.13 H.sub.17 NO.sub.4                                                               251.27   93   70   Cal. Obt.                                                                        62.14 62.14                                                                       6.82 6.80                                                                         5.57 5.56               222     CH.sub.3  C.sub.11 H.sub.13 NO.sub.4                                                               223.22   106  81   Cal.                                                                             59.18                                                                             5.87                                                                              6.28                                                                   Obt.                                                                             59.15                                                                             6.01                                                                              6.38                    223                                                                                     ##STR250##                                                                              C.sub.16 H.sub.21 NO.sub.4                                                               291.34   108  92   Cal. Obt.                                                                        65.96 66.17                                                                       7.27 7.58                                                                         4.81 5.01               224     C.sub.3 H.sub.7n                                                                         C.sub.13 H.sub.17 NO.sub.4                                                               251.27   88   78   Cal.                                                                             62.14                                                                             6.82                                                                              5.57                                                                   Obt.                                                                             62.16                                                                             6.53                                                                              5.80                    __________________________________________________________________________      ##STR251##                                                                                                         Melting  ELEMENTARY                                                            Point                                                                               Yield                                                                              ANALYSIS                         Code Number                                                                            R'.sub.6  Empirical Formula                                                                        Molecular Weight                                                                        (°C.)                                                                        %   %  C  H  N                       __________________________________________________________________________     230     Et        C.sub.12 H.sub.15 NO.sub.4                                                               237.25   86   81  Cal.                                                                              60.75                                                                             6.37                                                                              5.90                                                                  Obt.                                                                              60.60                                                                             6.21                                                                              5.83                    231                                                                                     ##STR252##                                                                              C.sub.14 H.sub.19 NO.sub.4                                                               265.30   98   85  Cal. Obt.                                                                         63.38 63.28                                                                       7.22 7.04                                                                         5.28 5.39               232                                                                                     ##STR253##                                                                              C.sub.15 H.sub.21 NO.sub.4                                                               279.33   80   82  Cal. Obt.                                                                         64.49 64.30                                                                       7.58 7.42                                                                         5.01 4.84               __________________________________________________________________________

The compounds of formula (I) were studied on laboratory animals and showed activities in the psychotropic field, as potential anti-depressants.

These activities were revealed in the following tests:

Test A: Potentiation in mice of generalized trembling caused by an interperitoneal injection (200 mg/kg) of dl-5-hydroxytryptophane, following the protocol described by C. Gouret and G. Raynaud in J. Pharmacol. (Paris), (1974), 5, 231.

Test B: Antagonism with respect to the ptosis observed one hour after an intravenous injection (2 mg/kg) of reserpine given to mice, following the protocol described by C. Gouret and J. Thomas in J. Pharmacol. (Paris), 1973, 4, 401.

The results of these two tests, as well as those of a well-know reference substance, Toloxatone, are collected in Table IV below:

                  TABLE VI                                                         ______________________________________                                         Compound                                                                       tested   Test A    Test B      Toxicity                                        Code     ED/50/    ED/50/      LD/50                                           Number   mg/kg/po  mg/kg/po    Mouse /mg/kg/po                                 ______________________________________                                         1        12.5      6.2                                                         2        12.5      8                                                           3        3.1       2.7         >2000                                           4        2.3       3.4                                                         5        4.7       9.5                                                         6        2.4       6                                                           7        --        7.4                                                         8        2.2       7.2                                                         9        --        25                                                          10       2.4       5.8                                                         11       4.2       6.2                                                         12       4.6       6                                                           13       3         2           >2000                                           14       2         3.1                                                         15       2.2       2                                                           16       1.7       1.5                                                         17       4.8       3.6                                                         18       4         4.25                                                        19       5.5       3.5                                                         20       8.8       3.7                                                         21       2.1       3.5                                                         22       --        3                                                           23       12        12.5                                                        24       9         12.5        >2000                                           25       15        25                                                          26       12.5      20                                                          27       25        44                                                          28       32        20                                                          29       45        50                                                          30       4.2       4.5                                                         31       6.5       3.6                                                         32       4.7       3.6                                                         33       9.4       4.5                                                         34       7         7.5                                                         35       19        6.5                                                         36       1.7       1.5                                                         37       1.9       2                                                           38       1.5       2                                                           39       1.75      1.6                                                         40       6.2       1.5                                                         41       6.2       4.5                                                         42       1.25      2                                                           43       15        17.5                                                        44       6.2       --                                                          45       45        50                                                          46       1.5       2                                                           47       18        36                                                          48       50        50                                                          49       0.5       0.4         2000                                            50       17.5      15                                                          51       27        50                                                          52       1.2       --          >2000                                           53       5         5.8                                                         54       14        12.5                                                        55       0.6       1.1                                                         56       --        3                                                           57       7.8       9                                                           58       50        8.8                                                         59       3.4       3.1                                                         60       30        --                                                          61       0.08      0.1         1500                                            62       3.6       2.4                                                         63       9.4       16.5                                                        64       --        4.5                                                         65       0.28      0.75                                                        66       4.7       6                                                           67       4.4       5.6                                                         68       5         6.2                                                         69       0.5       0.2                                                         70       0.8       0.6                                                         71       1         0.8                                                         72       0.8       1                                                           73       0.6       0.8                                                         74       4         6.2                                                         75       8         --                                                          76       2.1       6.2                                                         77       2.5       6.2         >2000                                           78       6.2       --                                                          79       6.2       2                                                           80       20        25                                                          81       24        25                                                          82       9.6       12                                                          83       12.5      6.2                                                         84       3         1.3                                                         85       3         2           1000                                            86       4.5       4.8                                                         87       29        44                                                          88       12.5      33                                                          89       12.5      12.5                                                        90       3         8                                                           91       4.5       5.5         >2000                                           92       30        50                                                          93       9         6                                                           94       1.5       1           >2000                                           95       50        35                                                          96       4.7       3.6                                                         177      8         15.5                                                        97       3.9       3.2                                                         98       12.5      12.5                                                        99       50        30          >2000                                           111      0.28      --                                                          100      6.2       --                                                          101      18        --                                                          102      6.2       --                                                          103      5         6                                                           104      6.2       --                                                          105      6.2       --                                                          106      6.2       --                                                          107      --        12                                                          108      5.6       --                                                          109      0         1                                                           110      0.3       --                                                          112      0.1       0.15                                                        TOL-                                                                           OXA-                                                                           TONE     60        50                                                          114      3.7       2           >2000                                           115      3.8       4.8                                                         116      1.6       0.95                                                        117      1.2       1.5                                                         118      1         0.1         >2000                                           119      --        8                                                           120      --        3                                                           121      11        8                                                           122      6.8       6.2                                                         123      2         1.4         >2000                                           124      --        0.6                                                         125      5         3.5                                                         126      4.4       1.8                                                         127      5         4.3                                                         128      7.2       4.8                                                         129      7.5       12                                                          130      6.2       9.6                                                         131      12        31                                                          132      3         2           >2000                                           133      6         5.2                                                         134      --        3.9                                                         135      --        4.2                                                         136      --        31                                                          137      --        6                                                           138      --        6                                                           142      18        17.5                                                        143      12.5      12                                                          144      2.2       1.1                                                         145      8.5       12                                                          146      5         12.5                                                        147      1.5       2.6                                                         148      2.2       --                                                          149      6         --                                                          152      18        15.5                                                        153      3.8       4                                                           154      19        17.5                                                        155      9.6       3                                                           156      0.47      0.3                                                         157      4.7       6.2                                                         158      6         6                                                           159      5.2       4.8                                                         160      --        4.2                                                         161      1.1       0.36        >2000                                           162      0.54      1.55                                                        163      1.15      8                                                           170      12.5      16                                                          171      19.5      25                                                          172      --        8.6                                                         173      --        4.7                                                         175      5.8       9.6                                                         176      4         4                                                           150      0.7       0.5                                                         151      5.2       5                                                           164      3.4       3.4                                                         165      6.8       4.7                                                         166      3.8       3.4                                                         167      3.7       3                                                           168      25        16          >1000                                           169      3         4.1         >1000                                           174      3         3.5                                                         113      3.2       3.5                                                         178      33        28          >1000                                           179      4.5       7           >1000                                           180      7.4       7.8         1000  (20%)                                     181      4         9           >1000                                           182      3.7       5.8         >1000                                           183      1.9       2.4         >1000                                           184      1.2       0.72        >1000                                           185      12        7           >1000                                           186      3         3           >1000                                           187      2.7       1.3         >1000                                           188      0.3       0.4         --                                              189      2.6       0.9         >1000                                           190      1         0.23        >1000                                           191      0.4       0.38        1000  (40%)                                     192      5.8       6           >1000                                           193      19        30          --                                              194      6.4       5.8         --                                              195      1.2       2.2         >1000                                           196      --        0.55        >1000                                           197      2.2       6.7         >1000                                           198      40        34          >1000                                           199      0.31      --          >1000                                           200      1.7       --          >1000                                           201      7.4       6.8         >1000                                           202      10        10          > 1000                                          203      5.2       1.4         1000  (40%)                                     204      50        40          1000  (40%)                                     205      10.1      3           >1000                                           206      6         4.3         >1000                                           207      9.1       7.6         >1000                                           208      10        4.2         >1000                                           209      7         6.7         1000  (20%)                                     210      26        7.4         >1000                                           211      2         1.2         1000  (20%)                                     212      4.3       12          1000  (40%)                                     213      3         2           1000  (100%)                                    214      0.84      1.8         1000  (40%)                                     215      6.2       10          >1000                                           216      5         3           1000  (80%)                                     217      1         1           --                                              218      7.2       13.5        >1000                                           219      7         13.5        >1000                                           220      50        50          >1000                                           234      0.6       4           >1000                                           ______________________________________                                    

As can be seen from the results shown in Table IV, the compounds of formula (I) have an activity greater than that of the reference compound.

They are indicated in endogenous and exogenous depressive conditions and will be administered orally in the form of tablets, pills or capsules, at a dosage of 50 to 500 mg/day on average, of active substance.

They will also be administered in the form of an injectable solution at the rate of 5-50 mg/day of active substance, the solvent used being formed by binary or ternary mixtures containing for example water, polypropyleneglycol or polyethyleneglycol (quality: 300-400), or any other physiologically acceptable solvent, the relative porportions of the different solvents being adjusted with respect to the dose administered. 

I claim:
 1. A compound having the formula ##STR254## in which R₂ is --CH₂ OH, --CH₂ OR₁₆ wherein R₁₆ is alkyl having from 1 to 3 carbon atoms, or --CH₂ OCOR₁₈, wherein R₁₈ is methyl or ethyl, and when R₂ is --CH₂ OH, R is selected from the group consisting of alkoxy having from 2 to 5 carbon atoms, cyclopentylmethoxy, cyclohexylmethoxy, (cyclohexen-1-yl)methoxy, (tetrahydropyran-4-yl)methoxy, cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 4-cyanobutoxy, ##STR255## wherein R₁₅ is 3--Cl, 4--Cl, 3--F, 4--F, 3--NO₂, 3--CN or 3--CF₃, ##STR256## when R₂ is --CH₂ OR₁₆, R is selected form the group consisting of 3-methylbutoxy, cyclopentylmethoxy, cyclohexylmethoxy, 4-cyanobutoxy, ##STR257## wherein R₁₇ is CN or NO₂, 3-cyano-5-nitrobenzyloxy or pyridinyl-3-methoxy; and when R₂ is --CH₂ OCOR₁₈, R is cyclohexylmethoxy or ##STR258## wherein R₁₇ is CN or NO₂.
 2. A compound as claimed in claim 1 in which R₂ is --CH₂ OH.
 3. A compound as claimed in claim 1 in which R₂ is --CH₂ OR₁₆.
 4. A compound as claimed in claim 1 in which R₂ is --CH₂ OCH₃ and R is ##STR259##
 5. A compound as claimed in claim 1 in which R₂ is --CH₂ OCH₃ and R is --O--(CH₂)₄ --CN.
 6. A compound as claimed in claim 1 in which R₂ is --CH₂ OCOR₁₈.
 7. A pharmaceutical composition for treating depression comprising a therapeutically effective amount of a compound as claimed in claim 1 and a pharmacologically acceptable carrier. 